Combination Therapy for the Treatment of Diffuse Midline Gliomas
PNOC022
A Combination Therapy Trial Using an Adaptive Platform Design for Children and Young Adults With Diffuse Midline Gliomas (DMGs) Including Diffuse Intrinsic Pontine Gliomas (DIPGs) at Initial Diagnosis, Post-Radiation Therapy and at Time of Progression
3 other identifiers
interventional
360
6 countries
32
Brief Summary
This phase II trial determines if the combination of ONC201 with different drugs is effective for treating participants with diffuse midline gliomas (DMGs). Despite years of research, little to no progress has been made to improve outcomes for participants with DMGs, and there are few treatment options. This trial will utilize an adaptive platform design in that the different treatment arms for each cohort will be opened and closed based on ongoing preclinical investigation as well as evolving outcome data from the trial. Novel agents will be continuously added to this study as pre-clinical data emerge to suggest additive or synergistic activity when combined ONC201. Should a novel agent not have an RP2D at the time of incorporation into this study, a phase 1 lead-in will be performed prior to initiation of combination therapy (via study amendment).
Trial Health
Trial Health Score
Automated assessment based on enrollment pace, timeline, and geographic reach
participants targeted
Target at P75+ for phase_2
Started Oct 2021
Longer than P75 for phase_2
32 active sites
Health score is calculated from publicly available data and should be used for screening purposes only.
Trial Relationships
Click on a node to explore related trials.
Study Timeline
Key milestones and dates
First Submitted
Initial submission to the registry
August 10, 2021
CompletedFirst Posted
Study publicly available on registry
August 18, 2021
CompletedStudy Start
First participant enrolled
October 20, 2021
CompletedPrimary Completion
Last participant's last visit for primary outcome
December 31, 2027
ExpectedStudy Completion
Last participant's last visit for all outcomes
June 30, 2029
December 17, 2025
December 1, 2025
6.2 years
August 10, 2021
December 11, 2025
Conditions
Outcome Measures
Primary Outcomes (6)
Progression-free survival at 6 months (PFS6) - Cohorts 1A, 1B Only
Percentage of participants alive and free from progression at 6 months after the diagnosis. The primary analysis for PFS6 is based on the intention to treat (ITT) population, according to treatment arm assignment. PFS6 is estimated using the Kaplan-Meier method with exact confidence intervals for each cohort and arm. Participants with unknown progression status at 6 months are considered failures (i.e., progressed) for the PFS6 analysis.
6 months after diagnosis
Progression-free survival at 6 months (PFS6) - Cohorts 2A, 2B Only
Percentage of participants alive and free from progression at 6 months after diagnosis. The primary analysis for PFS6 is based on the intention to treat (ITT) population, according to treatment arm assignment. PFS6 is estimated using the Kaplan-Meier method with exact confidence intervals for each cohort and arm. Participants with unknown progression status at 6 months are considered failures (i.e., progressed) for the PFS6 analysis.
6 months after diagnosis
Overall survival at 7 months (OS7) - Cohort 3A & 3B Only
OS7 is defined as the percentage of participants alive at 7 months after the initiation of the combination of the backbone (i.e., ONC201) with a novel agent given in the maintenance phase of therapy. The primary analysis for OS7 is based on the ITT population, according to treatment arm assignment. OS7 is estimated using the Kaplan-Meier method with exact confidence intervals for each cohort and arm. Participants with unknown survival status at 7 months are considered failures (i.e., dead) for the OS7 analysis.
7 months after administration of ONC201 in the maintenance phase
Proportion of participants reporting dose-limiting toxicities (DLTs) (Cohort 4)
The safety and tolerability of ONC201 at a previously untested dose will be measured by the proportion of participants reporting a DLT within the first cycle of treatment.
Up through the first cycle of maintenance therapy, approximately 8 months
Number of participants requiring dose modification through first cycle of maintenance (Cohort 5)
The safety and tolerability of ONC201 in combination with targeted therapies will be measured by the number of participants reporting dose modification during first cycle.
Up through the first cycle of maintenance therapy, approximately 8 months
Maximum tolerated number of intratumor infusions of DNX-2401, with a maximum of 6, in participants with thalamic or pontine DMG who have completed radiotherapy (Cohort 6)
The safety and tolerability of DNX-2401 at Dose Level 1 (5 × 10\^10 viral particles) will be measured by the proportion of participants reporting a DLT.
A maximum of 6 infusions will be administered every 30 days - approximately 8 months
Study Arms (6)
NOT CURRENTLY ENROLLING - ARM 2: ONC201 (Day -1), Radiation+ONC201, Paxalisib+ONC201
EXPERIMENTALParticipants may receive a safety lead in of ONC201. During the trial validation phase, participants without prior biopsy receive ONC201 PO on day -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, participants without prior radiation therapy or have disease progression after radiation therapy undergo weekly radiation therapy and receive ONC201 PO weekly during radiation therapy. During the maintenance phase, participants receive ONC201 PO weekly and paxalisib PO daily (QD). Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity
NOT CURRENTLY ENROLLING - ARM 4: ONC201 (Day -1,-2), Radiation+ONC201, Paxalisib+ONC201
EXPERIMENTALParticipants may receive a safety lead in of ONC201. During the trial validation phase, participants without prior biopsy receive ONC201 PO on days -2 and -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, participants may receive ONC201 PO weekly during radiation therapy. During the maintenance phase, participants receive ONC201 PO weekly and paxalisib PO QD. Cycles repeat every 28 days (4 weeks) in the absence of adverse events or unacceptable toxicity
NOT CURRENTLY ENROLLING - ARM 6: Paxalisib (Day -1), Radiation+Paxalisib , Paxalisib+ONC201
EXPERIMENTALParticipants may receive a safety lead in of ONC201. During trial validation phase, participants without prior biopsy receive paxalisib PO on day -1 prior to standard of care biopsy. During the radiation/re-irradiation phase, participants without prior radiation therapy or have disease progression after radiation therapy undergo weekly radiation therapy and receive paxalisib PO daily during radiation therapy. During the maintenance phase, participants receive ONC201 PO weekly and paxalisib PO QD. Cycles repeat every 28 days (4 weeks) in the absence of adverse events of unacceptable toxicity
Cohort 4 - Dose Escalation, Starting Dose 2 (625mg ONC201)
EXPERIMENTALParticipants will receive a safety lead in of 625mg (or weight-adjusted adult equivalent RP2D for pediatrics) of ONC201 on Day 1 and 2 of each week. During the target validation phase, participants without prior biopsy receive ONC201 PO on days -2 and -1 prior to standard of care biopsy. For participants receiving non-interventional radiation/re-irradiation per standard of care treatment, participants will receive 625 mg as the starting dose of ONC201 Days 1 and 2 on a weekly basis during radiation. Cycles repeat every 28 days (4 weeks) in the absence of adverse events or unacceptable toxicity
Cohort 5 - ONC201 + Targeted therapies
EXPERIMENTALParticipants will receive a starting dose of 625mg (or weight-adjusted adult equivalent RP2D for pediatrics) of ONC201 on Day 1 and 2 of each week in combination with targeted agents to be selected from approved/available agents based on a rational therapy approach guided by molecular data from the tumor tissue or cerebral spinal fluid (CSF). For participants receiving non-interventional radiation/re-irradiation per standard of care treatment, prior to starting the combination therapy, participants will receive 625 mg as the starting dose of ONC201 Days 1 and 2 on a weekly basis during radiation. Observations and schedule of events will be issued based on the chosen agent determined to best fit the molecular profile (e.g. BRAFV600E, PDGFRA, FGFR1, NF1).
Cohort 6 - DNX-2401 Repeated Intratumoral Administration
EXPERIMENTALParticipants will receive repeated DNX-2401 intratumoral infusions every 30 days, for a maximum of six injections. During Infusion 1 and Infusion 3, participants will have a biopsy for tumor tissue collection.
Interventions
Given orally (PO)
Undergo radiation therapy
Given PO
DNX-2401 is an oncolytic adenovirus that will be administered through direct intratumoral infusion of DNX-2401 via a specialized Neuro Ventricular Cannula.
Eligibility Criteria
You may qualify if:
- COHORT 1A AND 1B:
- New diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors. In cohort 1B, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma Histone 3 lysine 27 - mutant (H3K27M); World Health Organization (WHO) grade III and IV H3 wildtype gliomas.
- Must be within 6 weeks of diagnosis to begin standard of care radiation therapy on study.
- COHORT 2A AND 2B:
- Diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors, who have complete standard-of-care radiation therapy. In Cohort 2B, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma H3K27M mutant; WHO grade III and IV H3 wildtype gliomas.
- Participants must be within 4-14 weeks of completion of radiation. Radiation should have started within 6 weeks of diagnosis.
- COHORT 3A AND 3B:
- Diagnosis of recurrent DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors, who have complete standard-of-care radiation therapy. In cohort 3B, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG including diffuse midline glioma H3K27M mutant; WHO grade III and IV H3 wildtype gliomas.
- Participants must have evidence of progression and not have received any treatment for this progression and have not previously received re-irradiation.
- COHORT 4A AND 4B:
- Diagnosis of DMG with imaging and/or pathology consistent with a DMG, including spinal cord tumors. In cohort 4B\^1, previous tumor tissue confirmation of DMG is mandatory and pathology must be consistent with a DMG diffuse midline glioma H3K27-altered.
- Not currently eligible for any other clinical trials that include administration of ONC201.
- Cohort 4A\^1 and 4B\^1 (participants with newly diagnosed DMG prior to radiation): Must be able to begin standard of care radiation therapy on study within 6 weeks of diagnosis.
- Cohort 4A\^2 and 4B\^2 (participants with newly diagnosed DMG who have completed radiation): Participants must be within 4-14 weeks of completion of radiation and not have received additional therapy beyond completion of radiation therapy. Radiation should have started within 6 weeks of diagnosis.
- Cohort 4A\^3 and 4B\^3 (participants with DMG at progression): Participants must have evidence of progression and not have received any treatment for this progression and have not previously received re-irradiation.
- +62 more criteria
You may not qualify if:
- COHORT 1A AND 1B:
- Prior exposure to radiation therapy.
- Thalamic and Cerebellar H3K27M DMG.
- COHORT 2A AND 2B:
- Thalamic and Cerebellar H3K27M DMG that has undergone standard radiation without concurrent therapy (other than temozolomide).
- COHORT 1A AND 2A:
- Deemed not appropriate for tissue resection/biopsy.
- COHORT 3A AND 3B:
- Prior exposure to re-irradiation for tumor progression.
- Thalamic and cerebellar H3K27M mutant DMG.
- COHORT 4A AND 4B:
- Cohort 4A\^1and 4B\^1: Prior exposure to radiation therapy Cohort 4A\^3 and 4B\^3: Prior exposure to re-irradiation for tumor progression
- Thalamic and cerebellar H3K27M mutant DMG, except those who received ONC201/ONC026 from alternative source prior to 2024 or US patients enrolled while the accelerated approval new drug application for dordaviprone to treat recurrent H3 K27M-mutant diffuse glioma is under review by US FDA.
- Cohort 4A\^1and 4B\^1: Prior exposure to radiation therapy
- Cohort 4A\^3 and 4B\^3: Prior exposure to re-irradiation for tumor progression
- +34 more criteria
Contact the study team to confirm eligibility.
Sponsors & Collaborators
- University of California, San Franciscolead
- The Chad-Tough Defeat DIPG Foundationcollaborator
- Mithil Prasad Foundationcollaborator
- Storm the Heavens Fundcollaborator
- National Institute of Neurological Disorders and Stroke (NINDS)collaborator
- Jazz Pharmaceuticalscollaborator
- Neeve Kolte and Brave Ronil Foundationcollaborator
- Will Meeker Foundationcollaborator
- CV Biomanufacturingcollaborator
Study Sites (32)
University of Alabama at Birmingham
Birmingham, Alabama, 35233, United States
Children's Hospital Los Angeles
Los Angeles, California, 90027, United States
University of California, San Diego / Rady Children's Hospital, San Diego
San Diego, California, 92123, United States
University of California, San Francisco
San Francisco, California, 94143, United States
Children's National Hospital
Washington D.C., District of Columbia, 20010, United States
Ann & Robert H. Lurie Children's Hospital of Chicago
Chicago, Illinois, 60611, United States
Indiana University Riley Children's Hospital
Indianapolis, Indiana, 46202, United States
Johns Hopkins University
Baltimore, Maryland, 21287, United States
Dana-Farber Cancer Institute Harvard University
Boston, Massachusetts, 02215-6024, United States
University of Michigan
Ann Arbor, Michigan, 48109, United States
Children's Hospital Minnesota
Minneapolis, Minnesota, 55404, United States
Washington University in St. Louis
St Louis, Missouri, 63110, United States
Hackensack Meridian Health
Hackensack, New Jersey, 07601, United States
New York University
New York, New York, 10016, United States
Duke University
Durham, North Carolina, 27708, United States
Nationwide Children's Hospital
Columbus, Ohio, 43205, United States
Children's Hospital of Philadelphia
Philadelphia, Pennsylvania, 19104, United States
University of Utah
Salt Lake City, Utah, 84101, United States
Seattle Children's Hospital
Seattle, Washington, 98101, United States
John Hunter Children's Hospital
New Lambton Heights, New South Wales, 2305, Australia
The Children's Hospital at Westmead
Westmead, New South Wales, 2152, Australia
Queensland Children's Hospital
South Brisbane, Queensland, Australia
Monash Children's Hospital
Clayton, Victoria, 3168, Australia
The Royal Children's Hospital Melbourne
Melbourne, Victoria, 3052, Australia
Perth Children's Hospital
Nedlands, Washington, 6009, Australia
Women and Children's Hospital
Adelaide, Australia
Sydney Children's Hospital
Sydney, 2031, Australia
Sheba Medical Center
Tel Litwinsky, Ramat Gan, Israel
Shaare Zedek Medical Center
Jerusalem, 9103102, Israel
Princess Maxima Center
Utrecht, Netherlands
Starship Children's Hospital
Auckland, New Zealand
The University Children's Hospital in Zurich
Zurich, Switzerland
Related Publications (3)
Jackson ER, Duchatel RJ, Staudt DE, Persson ML, Mannan A, Yadavilli S, Parackal S, Game S, Chong WC, Jayasekara WSN, Grand ML, Kearney PS, Douglas AM, Findlay IJ, Germon ZP, McEwen HP, Beitaki TS, Patabendige A, Skerrett-Byrne DA, Nixon B, Smith ND, Day B, Manoharan N, Nagabushan S, Hansford JR, Govender D, McCowage GB, Firestein R, Howlett M, Endersby R, Gottardo NG, Alvaro F, Waszak SM, Larsen MR, Colino-Sanguino Y, Valdes-Mora F, Rakotomalala A, Meignan S, Pasquier E, Andre N, Hulleman E, Eisenstat DD, Vitanza NA, Nazarian J, Koschmann C, Mueller S, Cain JE, Dun MD. ONC201 in Combination with Paxalisib for the Treatment of H3K27-Altered Diffuse Midline Glioma. Cancer Res. 2023 May 17:OF1-OF17. doi: 10.1158/0008-5472.CAN-23-0186. Online ahead of print.
PMID: 37195023DERIVEDJackson ER, Duchatel RJ, Staudt DE, Persson ML, Mannan A, Yadavilli S, Parackal S, Game S, Chong WC, Jayasekara WSN, Le Grand M, Kearney PS, Douglas AM, Findlay IJ, Germon ZP, McEwen HP, Beitaki TS, Patabendige A, Skerrett-Byrne DA, Nixon B, Smith ND, Day B, Manoharan N, Nagabushan S, Hansford JR, Govender D, McCowage GB, Firestein R, Howlett M, Endersby R, Gottardo NG, Alvaro F, Waszak SM, Larsen MR, Colino-Sanguino Y, Valdes-Mora F, Rakotomalala A, Meignan S, Pasquier E, Andre N, Hulleman E, Eisenstat DD, Vitanza NA, Nazarian J, Koschmann C, Mueller S, Cain JE, Dun MD. ONC201 in combination with paxalisib for the treatment of H3K27-altered diffuse midline glioma. Cancer Res. 2023 May 5;83(14):2421-37. doi: 10.1158/0008-5472.CAN-23-0186. Online ahead of print.
PMID: 37145169DERIVEDPrzystal JM, Cianciolo Cosentino C, Yadavilli S, Zhang J, Laternser S, Bonner ER, Prasad R, Dawood AA, Lobeto N, Chin Chong W, Biery MC, Myers C, Olson JM, Panditharatna E, Kritzer B, Mourabit S, Vitanza NA, Filbin MG, de Iuliis GN, Dun MD, Koschmann C, Cain JE, Grotzer MA, Waszak SM, Mueller S, Nazarian J. Imipridones affect tumor bioenergetics and promote cell lineage differentiation in diffuse midline gliomas. Neuro Oncol. 2022 Sep 1;24(9):1438-1451. doi: 10.1093/neuonc/noac041.
PMID: 35157764DERIVED
MeSH Terms
Conditions
Interventions
Condition Hierarchy (Ancestors)
Intervention Hierarchy (Ancestors)
Study Officials
- PRINCIPAL INVESTIGATOR
Sabine Mueller, MD, PhD
University of California, San Francisco
Central Study Contacts
Study Design
- Study Type
- interventional
- Phase
- phase 2
- Allocation
- RANDOMIZED
- Masking
- NONE
- Purpose
- TREATMENT
- Intervention Model
- PARALLEL
- Sponsor Type
- OTHER
- Responsible Party
- PRINCIPAL INVESTIGATOR
- PI Title
- Principal Investigator
Study Record Dates
First Submitted
August 10, 2021
First Posted
August 18, 2021
Study Start
October 20, 2021
Primary Completion (Estimated)
December 31, 2027
Study Completion (Estimated)
June 30, 2029
Last Updated
December 17, 2025
Record last verified: 2025-12
Data Sharing
- IPD Sharing
- Will share
- Shared Documents
- STUDY PROTOCOL
Individual participant data after de-identification will be shared with study collaborators